Method for producing unsymmetrically substituted biphenyls

ABSTRACT

The invention concerns a method for the production of unsymmetrically substituted cyanobiphenyls by the slow addition of an aryl Grignard compound to an optionally substituted bromobenzonitrile in the presence of a palladium complex catalyst.

This application is a 371 of PCT/IB97/00266 filed on Feb. 24, 1997.

This invention concerns a method for producing unsymmetricallysubstituted biphenylcarbonitriles.

Some angiotensin II inhibitors contain a biphenyl residue as part of themolecule. The synthesis of these pharmaceutically active substancesrequires the use of unsymmetrically substituted biphenyls as startingmaterials or intermediates from which the final synthesis of the targetmolecule can be carried out. There is therefore a requirement for asimple and reliable method for the synthesis of unsymmetricallysubstituted biphenyls, which can be meaningfully incorporated into aneconomical overall process. This requires in particular a highselectivity and high yield. A special significance in this connectionattaches to biphenyl derivatives bearing a cyano function.

Unsymmetrically substituted biphenyl- and biaryl-compounds are alsosuitable for use as liquid crystal compounds and as a part ofelectro-optical components, in particular for use in non-linear optics.

Methods which have been suggested for the synthesis of unsymmetricallysubstituted cyanobiphenyls include the reaction of organo-boron, zinc ortin compounds with bromobenzonitriles [J.Organometallic Chem.390(1990)389-3981]. The palladium-catalysed coupling of an aryl Grignardcompound with an iodo-substituted benzonitrile has also been described.A method for the synthesis of 4'-methylbiphenyl-2-carbonitrile has beendisclosed [EP 566468 A] in which a halobenzonitrile is treated with4-methylphenyl-magnesium halide in the presence of a manganese salt ascatalyst. These methods suggest that the very low yields observed underpalladium catalysis are open to considerable improvement. For example,the authors of EP 566468 A saw a yield of only 1% on the reaction of 2.2equivalents of 4-methylphenylmagnesium bromide with 2-bromobenzonitrilein the presence of catalytic amounts of tetrakis(triphenylphosphine)-palladium over 6 hours at 65° C. In thisinvestigation the reactants were mixed together all at once.

On theoretical grounds, it would be expected that the coupling of anaryl Grignard compound with a haloaryl compound withelectron-withdrawing functionality would produce the desired biarylcoupling-product in high selectivity and with high yield [seeJ.Organometallic Chem. 390(1990)389-398, especially Table 1 on page391]. In the present state of the art, this requires that on addition ofthe Grignard reagent the carbon-halogen bond of the aryl halide withwhich the Grignard reagent reacts is considerably more reactive than anyother electron-accepting groups which may be present in the substratemolecule. These considerations in practice exclude the use ofbromobenzonitrile as a coupling partner, if high selectivity and highyield are to be achieved.

The present invention comprises a simple to carry out method for thesynthesis of unsymmetrically substituted cyanobiphenyl and cyanobiarylcompounds in high selectivity and with high yield. A further object ofthe invention is to make possible a general method for obtainingcompounds incorporating a biphenyl or biaryl structure. In particular, ahighly selective, simple and economical synthesis of the unsymmetricallysubstituted cyanobiphenyl compounds would make possible a simplesynthesis of such target molecules as angiotensin II inhibitors.

We have now found that by slow addition (i.e. addition over a relativelylong time scale) of a solution of an aryl Grignard compound to areaction medium containing a bromobenzonitrile and a suitable palladiumcomplex catalyst coupling takes place with as the main reaction theformation of biphenylcarbonitrile. The main reaction resulting when thereactants are mixed all at once, i.e. the addition of the Grignardcompound to the nitrile function, is by this means almost entirelysuppressed. The formation of imines (and after hydrolysis,benzophenones) is not observed to any significant extent.

The high selectivity arising from this method, which leads almostexclusively to the desired biphenylcarbonitrile, is surprising on thebasis of current knowledge. Further advantages of the method of theinvention include simplicity, avoidance of loss of material, and a highyield.

According to the invention there is provided a method for the synthesisof unsymmetrically substituted biphenyls of the general formula ##STR1##where R=H, alkyl, alkoxy, F, Cl or 4-phenylmethoxy by thepalladium-catalysed coupling of an aryl Grignard compound of the generalformula ##STR2## where R=H, alkyl, alkoxy, F, Cl or 4-phenylmethoxy;X=Cl, Br or I, in which the ring bearing substituent R may also havefurther substituents, with bromobenzonitrile (which may bear furthersubstituents), at 10-100° C., characterized in that the Grignardcompound is added slowly over a period of at least 30 minutes and thepalladium catalyst is added at a concentration of 0.1 to 20.0% molarbased on the bromobenzonitrile.

Slow addition in the manner of the invention has the effect that thereactants are not immediately brought into contact with one another bymixing, but that the addition of the Grignard compound to thebromobenzonitrile is controlled and takes place over a longertime-scale. In contrast, the effect of immediate addition is that thereactants are mixed together over a time-scale of (for example) lessthan ten minutes. As our investigations have shown, such a method doesnot lead to the production of the desired unsymmetrically substitutedbiphenylcarbonitrile in either high yield or high selectivity. Slowaddition means that (for example) the Grignard compound is added to 0.5to 2 equivalents of the bromobenzonitrile over at least 30 minutes.Simple experiments may be required here to optimise the addition time.The addition time for the Grignard compound may be 1-24 hours. It isusually in the range 4-18, preferably 8-10, hours. In any case, theaddition rate is so adjusted that concurrent formation of imines andbenzophenones is minimised. This time scale also depends on the amountand nature of the catalyst added. A range of palladium catalysts issuitable for the purpose. As a rule the concentration of the catalystshould be 0.1 to 20.0% molar (based on the bromobenzonitrile),preferably 1.0 to 2.0% molar.

The aryl Grignard compounds used in the invention have the generalformula ##STR3## where R=H, alkyl, alkoxy, F, Cl or 4-phenylmethoxy;X=Cl, Br or I. The aromatic ring may bear further substituents, so longas they do not interfere with the reactivity of the Grignard function.In particular, acetal and alkyl groups do not interfere with thereaction. "Alkyl" here in principle includes any type of substituted orunsubstituted 1-30C alkyl group or 3-20C cycloalkyl group. Ourinvestigations have shown that straight or branched chain alkyl groupscan be used with an upper limit somewhere between 25 and 30 carbonatoms. The bromobenzonitrile can also bear other substituentscorresponding to the above definitions, with obvious limitations imposedby undesirable reactivity or steric hindrance.

The yield of the desired unsymmetrically substituted biphenyls isusually higher by the method of the invention than by methods of theprior art. Reactions carried out as described, in contrast to most ofthe previously described synthetic routes, require no auxiliary base.This results in less effluent and a simpler process.

The essential point of the invention is the addition time of the arylGrignard compound solution to the reaction medium containing the othercomponents, which has crucial significance for the course of thereaction. As shown in Table 1 below the reaction of4-methoxyphenylmagnesium bromide with 4-bromobenzonitrile catalysed by2% (molar) palladium acetate/triphenylphosphine, with immediate thereaction of 4-methoxyphenylmagnesium bromide with 4-bromobenzonitrilecatalysed by 2% (molar) palladium acetate/triphenylphosphine, withimmediate mixing of the reactants, produces a mixture of4'-methoxybiphenyl-4-carbonitrile and4-bromo-4'-methoxybenzophenoneimine in the ratio 1:3 [see ComparativeExample 2]. As expected, the main reaction is addition of the Grignardcompound to the nitrile function. Longer addition times skew the productspectrum more and more in the direction of the biphenyl compound, untilat an addition time of several hours the biphenylcarbonitrile is formedwith high selectivity.

                  TABLE 1                                                         ______________________________________                                        Product ratio against Grignard compound addition time.sup.a                       #STR4##                                                                       #STR5##                                                                      -                                                                              #STR6##                                                                       #STR7##                                                                      -       Addition time (hours)                                                                       Ratio (A:B).sup.b                                    ______________________________________                                          0 1:3                                                                         2 2:1                                                                         6 5:1                                                                         9 20:1                                                                      ______________________________________                                         Notes:                                                                        [a] T = 20-25° C.; tetrahydrofuran; 2% (molar) Pd(OAc).sub.2           /2PPh.sub.3 ; 1.1 equivalents of Grignard compound.                           [b] A:B yield ratio determined by HPLC. Total yield (A + B) exceeds 90%. 

Suitable catalysts include all Pd(0) complexes such as Pd(PPh₃)₄ whichare known to be catalytically active in reactions of the type which thisinvention concerns (often called Suzuki or Heck coupling). Thecatalytically active Pd(0) species can be generated in situ from Pd(II)compounds. In a preferred way of carrying out the reaction, thecatalytically active species is produced in situ by the addition of amixture of PdCl₂ and triphenylphosphine (in the molar ratio 1:2) underthe influence of the Grignard compound. The amount of catalyst addeddepends on the requirements of the particular system. As a rule thepalladium compound is added at a molar concentration of 0.1% to 20%relative to the benzonitrile. Larger amounts of catalyst do notadversely affect the course of the reaction, but are undesirable oneconomic grounds. As an example Table 2 illustrates the use of variousamounts of catalyst in the coupling of 4-(phenylmethoxy)phenylmagnesiumbromide with 4-bromobenzonitrile.

                  TABLE 2                                                         ______________________________________                                        Product ratio against amount of catalyst.sup.a                                    #STR8##                                                                       #STR9##                                                                      -                                                                              #STR10##                                                                     ##STR11##                                                                  ______________________________________                                                      4      >100:1                                                     2 >100:1                                                                      0.4 >100:1                                                                  ______________________________________                                         Notes:                                                                        [a] T = 67-69° C.; tetrahydrofuran; addition time of Grignard          compound (1.1 equivalents) 8-9 hours.                                         [b] molar % relative to 4bromobenzonitrile.                                   [c] yield ratio of C and D determined by HPLC; total yield (C + D) is         greater than 95%.                                                        

Any organic solvent inert towards the Grignard compound is a suitablereaction medium, for example tetrahydrofuran, 2-methyltetrahydrofuran,acyclic ethers or acetals. Tetrahydrofuran and 2-methyltetrahydrofuranare preferred.

The reaction temperature is in the range 10-100° C. The reactiontemperature preferably lies in the range of 20-80° C.

The molar ratio of bromobenzonitrile to Grignard compound is preferably2:1 to 1:2 and especially between 1:1 and 1:1.2 at which higher yieldsand better quality product may be obtained.

The method here described permits the synthesis of unsymmetricallysubstituted biphenylcarbonitriles with substituents at any position(ortho, meta or para). All functional groups on the bromobenzonitrilewhich are compatible with the Grignard function are allowable assubstituents. The examples below use alkyl, halogen and alkoxysubstituents.

The invention is further illustrated by means of the following Examples.

EXAMPLE 1

4-methoxyphenylmagnesium bromide (112 g, 16% solution intetrahydrofuran) is added dropwise over nine hours at 20-25° C. to asolution of 4-bromobenzonitrile (14 g), palladium (II) acetate (0.35 g),and triphenylphosphine (0.81 g) in tetrahydrofuran (100 ml). [HPLC:total yield >90%; 4'-methoxybiphenyl-4-carbonitrile to4-bromo-4'-methoxybenzophenoneimine ratio 20:1]. Water (20 ml) is addedand tetrahydrofuran removed under vacuum. The residue is extracted withtoluene (110 ml). Insoluble material is filtered off and the filtrateevaporated down. The crude product is recrystallised from ethanol togive 4'-methoxybiphenyl-4-carbonitrile (12 g, 75%) as a solid, m.pt102-104° C. ¹ H NMR (CDCL³):3.85 (s,3H), 6.99 (d,2H), 7.52 (d,2H), 7.62(d,2H), 7.68 (d,2H).

EXAMPLE 2

4-methoxyphenylmagnesium bromide (91 g, 14% solution in tetrahydrofuran)is added dropwise over 6 hours at 20-25° C. to a solution of4-bromobenzonitrile (10 g), palladium (II) acetate (0.25 g) andtriphenylphosphine (0.58 g) in tetrahydrofuran (80 ml). [HPLC: totalyield >90%; ratio 4'-methoxybiphenyl-4-carbonitrile to4-bromo-4'-methoxybenzophenoneimine 5:1].

EXAMPLE 3

4-methoxyphenylmagnesium bromide (91 g, 14% solution in tetrahydrofuran)is added dropwise at 20-25° C. over two hours to a solution of4-bromobenzonitrile (10 g), palladium (II) acetate (0.25 g) andtriphenylphosphine (0.58 g) in tetrahydrofuran (80 ml). [HPLC: totalyield >90%; ratio 4'-methoxybiphenyl-4-carbonitrile to4-bromo-4'-methoxybenzophenoneimine 2:1].

EXAMPLE 4

4-(phenylmethoxy)phenylmagnesium bromide 759 g, 25% solution intetrahydrofuran) is added dropwise over nine hours at 20-25° C. to asolution of 4-bromobenzonitrile (109 g), palladium (II) chloride (4.2 g)and triphenylphosphine (13 g) in tetrahydrofuran (420 ml). After coolingto room temperature and addition of water (340 ml), the tetrahydrofuranis distilled off under vacuum. Toluene (680 ml) is added and the aqueousphase separated at 85° C. The organic phase is filtered hot (80-85° C.).[HPLC: total yield >90%; ratio 4'-(phenylmethoxy)biphenyl-4-carbonitrileto 4-bromo-4'-(phenylmethoxy)benzophenone 10:1]. Toluene (340 ml) isdistilled off. On cooling to room temperature,4'-(phenylmethoxy)biphenyl-4-carbonitrile (110 g, 64%) crystallises out,m.pt. 146-148° C. ¹ H NMR (CDCl₃): 5.10(s,2H), 7.06 (d,2H), 7.32-7.47(m,5H), 7.52 (d,2H), 7.62 (d,2H), 7.68 (d,2H).

EXAMPLE 5

4-(phenylmethoxy)phenylmagnesium bromide (809 g, 27% solution intetrahydrofuran) is added dropwise over eight hours to a refluxingsolution of 4-bromobenzonitrile (128 g), palladium (II) chloride (0.50g) and triphenylphosphine (1.5 g) in tetrahydrofuran (500 ml). Aftercooling to room temperature and addition of water (400 ml),tetrahydrofuran is removed under vacuum. Toluene (800 ml) is added andthe aqueous phase removed at 85° C. The organic phase is filtered hot.[HPLC: total yield >95%; ratio 4'-(phenylmethoxy)biphenyl-4-carbonitrileto 4-bromo-4'-(phenylmethoxy)benzophenone >100:1]. Toluene (400 ml) isdistilled off. On cooling to room temperature,4'-(phenylmethoxy)biphenyl-4-carbonitrile (178 g, 89%) crystallises out.

EXAMPLE 6

4-(phenylmethoxy)phenylmagnesium bromide (108 g, 21% solution intetrahydrofuran) is added dropwise over eight hours to a refluxingsolution of 4-bromobenzonitrile (13 g), palladium (II) chloride (51 mg)and triphenylphosphine (150 mg) in tetrahydrofuran (50 ml). Aftercooling to room temperature and addition of water (40 ml),tetrahydrofuran is removed under vacuum. Ethanol (30 ml) and 25%hydrochloric acid (2 ml) are added and the mixture refluxed for twohours. [HPLC: total yield >95%; ratio4'-(phenylmethoxy)biphenyl-4-carbonitrile to4-bromo-4'(phenylmethoxy)benzophenone >100:1).

EXAMPLE 7

4-(phenylmethoxy)phenylmagnesium bromide (108 g, 21% solution intetrahydrofuran) is added dropwise over nine hours to a refluxingsolution of 4-bromobenzonitrile (13 g), palladium (II) chloride (0.25 g)and triphenylphosphine (0.75 g) in tetrahydrofuran (50 ml). Aftercooling to room temperature and addition of water (40 ml),tetrahydrofuran is removed under vacuum. Ethanol (30 ml) and 25%hydrochloric acid (2 ml) are added and the mixture refluxed for twohours. [HPLC: total yield >95%; ratio4'-(phenylmethoxy)biphenyl-4-carbonitrile to4-bromo-4'-(phenylmethoxy)benzophenone >100:11].

EXAMPLE 8

4-(phenylmethoxy)phenylmagnesium bromide (108 g, 21% solution intetrahydrofuran) is added dropwise over nine hours to a refluxingsolution of 4-bromobenzonitrile (13 g), palladium (II) chloride (0.51 g)and triphenylphosphine (1.5 g) in tetrahydrofuran (50 ml). After coolingto room temperature and addition of water (40 ml), tetrahydrofuran isremoved under vacuum. Ethanol (30 ml) and 25% hydrochloric acid (2 ml)are added and the mixture refluxed for two hours. [HPLC: totalyield >95%; ratio 4'(phenylmethoxy)biphenyl-4-carbonitrile to4-bromo-4'-(phenylmethoxy)benzophenone >100:1].

EXAMPLE 9

4-methylphenylmagnesium chloride (610 g, 21% solution intetrahydrofuran) is added dropwise over eight hours to a refluxingsolution of 2-bromobenzonitrile (140 g), palladium (II) chloride (1.4 g)and triphenylphosphine (4.0 g) in tetrahydrofuran (375 ml). [HPLC:4'methylbiphenyl-2-carbonitrile >95%,2-bromo-4'-methylbenzophenoneimine >0.2%]. After cooling to roomtemperature tetrahydrofuran is removed under vacuum. Water (100 ml) andtoluene (360 ml) are added. After separation of the aqueous phase, thecrude product is distilled at 110-112° C./0.1 mbar, to give4'-methylbiphenyl-2-carbonitrile (131 g, 88%) as a solid, m.pt. 50-52°C. ¹ H NMR (CDCL₃): 2.40(s,3H), 7.30(d,2H), 7.37-7.52(m,4H), 7.59-7.66(m.1H), 7.75(m,1H).

EXAMPLE 10

4-methylphenylmagnesium chloride (100 g, 20% solution intetrahydrofuran) is added dropwise over two hours to a refluxingsolution of 2-bromobenzonitrile (22 g), palladium (II) chloride (0.21 g)and triphenylphosphine (0.63 g) in tetrahydrofuran (60 ml). Aftercooling to room temperature and addition of water (40 ml),tetrahydrofuran is removed under vacuum. Ethanol (30 ml) and 25%hydrochloric acid (2 ml) are added and the mixture refluxed for twohours. [HPLC: total yield >90%; ratio 4'-methylbiphenyl-2-carbonitrileto 2-bromo-4'-methylbenzophenone 5.1].

EXAMPLE 11

4-methylphenylmagnesium chloride (111 g, 18% solution in2-methyltetrahydrofuran) is added dropwise over eight hours to arefluxing solution of 2-bromobenzonitrile (22 g), palladium (II)chloride (0.21 g) and triphenylphosphine (0.63 g) in2-methyltetrahydrofuran (60 ml). After cooling to room temperature andaddition of water (40 ml), 2-methyltetrahydrofuran is removed undervacuum. Ethanol (30 ml) and 25% hydrochloric acid (2 ml) are added andthe mixture refluxed for two hours. [HPLC: total yield >95%; ratio4'-methylbiphenyl-2-carbonitrile to 2-bromo-4'-methylbenzophenone 10:1].

EXAMPLE 12

4-methylphenylmagnesium chloride (10 g, 20% solution in diethoxymethane)is added dropwise over nine hours to a refluxing solution of2-bromobenzonitrile (22 g), palladium (II) chloride (0.21 g) andtriphenylphosphine (0.63 g) in diethoxymethane (60 ml). After cooling toroom temperature and addition of water (40 ml), diethoxymethane isremoved under vacuum. Ethanol (30 ml) and 25 % hydrochloric acid (2 ml)are added and the mixture refluxed for two hours. [HPLC: totalyield >95%; ratio 4'-methylbiphenyl-2-carbonitrile to2-bromo-4'-methylbenzophenone about 100:1].

EXAMPLE 13

4-methylphenylmagnesium chloride (49 g, 20% solution in tetrahydrofuran)is added dropwise over eight hours to a refluxing solution of3-bromobenzonitrile (10 g), palladium (II) acetate (2.4 g) andtriphenylphosphine (5.8 g) in tetrahydrofuran (200 ml). [HPLC: yield89-91%]. After cooling to room temperature tetrahydrofuran is removedunder vacuum. The residue is taken up in toluene/water (3:1) (200 ml )and the aqueous phase separated off. The solvent is removed bydistillation and the crude product purified by column chromatrography(Kieselgel 60; n-hezane/acetone 3:1) to give4'-methylbiphenyl-3-carbonitrile as a solid, m.pt. 59-61° C. ¹ H NMR(CDCl₃): 2.41(s,3H), 7.29(d,2H), 7.46(d,2H), 7.49-7.63(m,2H)7.77-7.85(m,2H).

EXAMPLE 14

4-methylphenylmagnesium chloride (98 g, 20% solution in tetrahydrofuran)is added dropwise over five hours to a refluxing solution of4-bromobenzonitrile (20 g), palladium (II) chloride (0.78 g) andtriphenylphosphine (2.3 g) in tetrahydrofuran (100 ml). [HPLC: yield91-93%]. After cooling to room temperature tetrahydrofuran is removedunder vacuum. The residue is taken up in toluene/water (1:1) (200 ml)and filtered. The aqueous phase is separated off. Solvent is removed bydistillation and the crude product recrystallised from ethanol to give4'-methylbiphenyl-4-carbonitrile as a solid, m.pt. 107-109° C. ¹ H NMR(CDCl₃): 2.41(s,3H), 7.29(d,2H), 7.49(d,2H), 7.66 (d,2H), 7.71 (d,2H).

EXAMPLE 15

2-methylphenylmagnesium bromide (82 g, 31% solution in tetrahydrofuran)is added dropwise over eleven hours to a refluxing solution of4-bromobenzonitrile (20 g), palladium (II) chloride (0.78 g) andtriphenylphosphine (2.3 g) in tetrahydrofuran (100 ml). [HPLC: yield92-94%]. After cooling to room temperature, tetrahydrofuran is removedunder vacuum. The residue is taken up in toluene/water (3:1) (300 ml)and the aqueous phase separated off. The solvent is removed bydistillation and the crude product purified by column chromatography onKieselgel 60 using n-hexane/acetone (3:1). This gives2'-methylbiphenyl-4-carbonitrile as an oil. ¹ H NMR (CDCl₃): 2.25(s,3H),7.10-7.32(m,4H), 7.43(d,2H), 7.71(d,2H).

EXAMPLE 16

3-methoxyphenylmagnesium bromide (95 g, 29% solution in tetrahydrofuran)is added dropwise over nine hours to a refluxing solution of4-bromobenzonitrile (20 g), palladium (II) chloride (0.78 g) andtriphenylphosphine (2.3 g) in tetrahydrofuran (200 ml). [HPLC: yield90-92%]. After cooling to room temperature the tetrahydrofuran isremoved under vacuum. The residue is taken up in toluene/water (3:1)(300 ml) and the aqueous phase separated off. The solvent is removed bydistillation and the crude product purified by column chromatography onKieselgel 60 using n-hexane/acetone (3:1). This gives3'-methoxybiphenyl-4-carbonitrile as an oil. ¹ H NMR (CDCl₃):3.87(s,3H), 6.94-6.98(m,1H), 7.10(t,1H), 7.14-7.19(m,1H), 7.40(t,1H),7.67(d,2H), 7.72(d,2H).

EXAMPLE 17

4-methoxyphenylmagnesium bromide (280 g, 15% solution intetrahydrofuran) is added dropwise over seven hours to a refluxingsolution of 2-bromobenzonitrile (32 g), palladium (II) chloride (1.3 g)and triphenylphosphine (3.8 g) in tetrahydrofuran (210 ml). [HPLC: yield94-95%]. After cooling to room temperature and the addition of water (50ml), tetrahydrofuran is removed under vacuum. The residue is extractedwith toluene (230 ml). Insoluble material is filtered off and thesolvent distilled off. The crude product is recrystallised from ethanolto give 4'-methoxybiphenyl-2-carbonitrile as a solid, m.pt. 82-83° C. ¹H NMR (CDCl₃): 3.90(s,3H), 7.02(d,2H), 7.36-7.52(m,4H), 7.59-7.65(m,1H),7.74(d,1H).

EXAMPLE 18

4-octyloxyphenylmagnesium bromide (124 g, 25% solution intetrahydrofuran) is added dropwise over ten hours to a refluxingsolution of 4-bromobenzonitrile (17 g), palladium (II) chloride (0.68 g)and triphenylphosphine (2.0 g) in tetrahydrofuran (100 ml). [HPLC: yield92-94%]. After cooling to room temperature tetrahydrofuran is removedunder vacuum. Water (20 ml) and toluene (150 ml) are added and themixture filtered hot (80-85 C.). The aqueous phase is separated off, andthe solvent removed by distillation. The crude product is recrystallisedfrom ethanol/n-hexane to give 4'-octyloxybiphenyl-4-carbonitrile as asolid. ¹ H NMR (CDCl₃): 0.89(t,3H), 1.29-1.50(m,10H), 1.81(quint.2H),4.00(t,2H), 6.99(d,2H), 7.52(d,2H), 7.63(d,2H), 7.68(d,2H).

EXAMPLE 19

4-chlorophenylmagnesium chloride (114 g, 18% solution intetrahydrofuran) is added dropwise over seven hours to a refluxingsolution of 4-bromobenzonitrile (20 g), palladium (II) chloride (0.78 g) and triphenylphosphine (2.3 g) in tetrahydrofuran (100 ml). [HPLC:yield 75-79%]. After cooling to room temperature tetrahydrofuran isremoved under vacuum. The residue is taken up in toluene/water (1:1)(200 ml) and filtered. The aqueous phase is separated off, and thesolvent removed by distillation. The crude product is recrystallisedfrom isopropanol/ethanol to give 4'-chlorobiphenyl-4-carbonitrile as asolid, m.pt. 128-130° C. ¹ H NMR (CDCl₃): 2.41(s,3H), 7.46(d,2H),7.53(d,2H), 7.65(d,2H), 7.74(d,2H).

EXAMPLE 20

2,5-dimethylphenylmagnesium bromide (84 g, 20% solution intetrahydrofuran) is added dropwise over five hours to a refluxingsolution of 4-bromo-2-methylbenzonitrile (16 g), palladium (II) chloride(0.57 g) and triphenylphosphine (1.7 g) in tetrahydrofuran (100 ml).[HPLC: yield 90-95%]. After cooling to room temperature tetrahydrofuranis removed under vacuum. The residue is taken up in toluene/water (1:1)(200 ml) and filtered. The aqueous phase is separated off, and thesolvent removed by distillation. The crude product is recrystallisedfrom ethanol to give 3,2',5'-trimethylbiphenyl-4-carbonitrile as asolid, m.pt. 96-97° C. ¹ H NMR (CDCl₃): 2.19(s,3H), 2.34(s,3H),2.58(s,3H), 6.99(s,1H), 7.08-7.25(m,3H), 7.62(d,1H).

Comparative Example 1

4-methoxyphenylmagnesium bromide (78 g, 15% solution in tetrahydrofuran)is added dropwise over two hours at 20-25° C. to a solution of4-bromobenzonitrile (10 g) in tetrahydrofuran (80 ml). After addition ofwater (20 ml), tetrahydrofuran is removed under vacuum. The residue isextracted with toluene (100 ml) and the solvent removed under vacuum.4-bromo-4'-methoxybenzophenoneimine (3.5 g, 34%) is isolated by columnchromatography on Kieselgel 60 using n-hexane/acetone (3:1). ¹ H NMR(CDCl₃): 3.84 (s,3H), 6.93(d,2H), 7.41-7.61(m,6H), 9.5(s,1H).

Comparative Example 2

4-methoxyphenylmagnesium bromide (91 g, 14% solution in tetrahydrofuran)is added over 30 seconds at 20-25° C. to a solution of4-bromobenzonitrile (10 g), palladium (II) acetate (0.25 g) andtriphenylphosphine (0.58 g) in tetrahydrofuran (80 ml). [HPLC: totalyield >90%; ratio 4'-methoxybiphenyl-4-carbonitrile to4-bromo-4'-methoxybenzophenoneimine 1:31].

From these Examples the following conclusions can be drawn:

in an uncatalysed reaction, even with slow addition of the benzonitrile,the competitive benzophenoneimine product is predominantly obtained [seeComparative Example 1]

the palladium-catalysed reaction with slow addition gives a clearpredominance of the desired product [see all Examples].

If necessary simple experiments should be carried out to determine whichcatalyst concentration is most suitable for the particular reactants.For a palladium-based catalyst such as PdCl₂ /2PPh₃ the concentrationlimit at an addition time of 6-10 hours is about 0.4% molar based onbromobenzonitrile. Above this concentration the displacement of thecourse of reaction is unequivocally in favour of the desired product.Obviously, deviations from the desired selectivity and yield arepossible according to the chosen solvent, reactants and reactiontemperature. These problems can however be controlled by choice of ahigher catalyst concentration or a longer addition time.

What is claimed is:
 1. A method for producing unsymmetricallysubstituted biphenyls of the general formula ##STR12## where R=H, alkyl,alkoxy, F, Cl or 4-phenylmethoxy by the palladium-catalysed coupling ofan aryl Grignard compound of the general formula ##STR13## where X=Cl,Br or I; R=H, alkyl, alkoxy, F, Cl or 4-phenylmethoxy and the ringbearing the R substituent is optionally further substituted, withoptionally substituted bromobenzonitrile comprising adding the Grignardcompound to the bromobenzonitrile slowly at 10-100° C., over a time spanof at least 30 minutes, said palladium catalyst being present at aconcentration of 0.1 to 20.0% molar based on the benzonitrile.
 2. Amethod as claimed in claim 1, wherein the addition time for the Grignardcompound is from 1 to 24 hours.
 3. A method as claimed in claim 1,wherein the addition time for the Grignard compound is from 4 to 18hours.
 4. A method as claimed in claim 1, wherein the addition time forthe Grignard compound is from 8 to 10 hours.
 5. A method as claimed inclaim 1, wherein the palladium concentration of the catalyst is 1.0 to2.0% molar based on the bromobenzonitrile.
 6. A method as claimed inclaim 1, wherein R is alkyl and has up to 30 carbon atoms.
 7. A methodas claimed in claim 6, wherein R is alkyl and has up to 20 carbon atoms.8. A method as claimed in claim 1, wherein R is a straight or branchedchain alkyl group or a cycloalkyl group.
 9. A method as claimed in claim1, wherein the aromatic ring of the Grignard compound is furthersubstituted by an acetal or alkyl group.
 10. A method as claimed inclaim 1, wherein the palladium catalyst is a Pd(0) complex.
 11. A methodas claimed in claim 10, wherein the Pd(0) complex is Pd(PPh₃)₄.
 12. Amethod as claimed in claim 1, wherein the coupling reaction is carriedout at a temperature in the range of 20 to 80° C.
 13. A method asclaimed in claim 1, wherein the bromobenzonitrile is further substitutedby an alkyl or alkoxy group, by halogen or by 4-phenylmethoxy.
 14. Amethod as claimed in claim 1, wherein the molar ratio ofbromobenzonitrile to Grignard compound is 2:1 to 1:2.
 15. A method asclaimed in claim 14, wherein the molar ratio of bromobenzonitrile toGrignard compound is between 1:1 and 1:1.2.